DESCRIPTION: Cardiac fibrosis naturally occurs following myocardial infarction (MI). While the fibrotic tissue that forms initially protects the heart from rupture, continued cardiac fibrosis leds to a progressive decrease in cardiac function, and advances the infarcted heart towards heart failure. Accordingly, a therapy that can inhibit cardiac fibrosis from progressing at different stages of post-MI will preserve cardiac function and prevent the heart from evolving towards heart failure. However, there is currently no clinically approved therapy available. Myofibroblasts, formed primarily through TGF? binding to the TGF? receptor IIs (TGF?RIIs) on cardiac fibroblasts, are responsible for cardiac fibrosis. As such, to prevent cardiac fibrosis fro progressing, it is essential to inhibit the TGF? pathway-mediated new myofibroblast formation, and to convert existing myofibroblasts back to cardiac fibroblasts. Yet current preclinical approaches, such as the systemic delivery of TGF? inhibitors or anti-TGF? antibodies, only decrease the content of active TGF? in the heart, but do not inhibit the binding of TGF? to TGF?RIIs, thus cannot fundamentally prevent myofibroblast formation. Besides, the systemic delivery causes dose-limiting side effects. While the use of TGF?RII inhibitors have the potential to prevent myofibroblast formation by blocking TGF? from binding to TGF?RIIs, most of them are not suitable for cardiac anti-fibrotic therapy due to the effective dosages being always above the toxic level. The fundamental goal of this project is to create a peptide-based, low toxicity TGF?RII inhibitor, and its delivery system to efficiently inhibit TGF? pathway-mediated cardiac fibrosis from progressing at different stages of post-MI, thus preventing cardiac function from progressive deterioration. In our preliminary studies, we have created a peptide based TGF?RII inhibitor ECG. It blocks the initial step of the TGF? pathway ? TGF? binding to TGF?RIIs. It specifically binds to the TGF?RIIs on cardiac fibroblasts without differentiating them into myofibroblasts. ECG also has a higher affinity for TGF?RIIs than TGF?. Therefore, once the ECG binds to TGF?RIIs, TGF? cannot bind to these receptors. ECG also pulls off those TGF? already bonded to TGF?RIIs and occupies the receptors by itself. As a result, ECG is able to prevent TGF?-induced myofibroblast differentiation, and revert myofibroblasts back to cardiac fibroblasts. To deliver ECG into infarcted hearts with high ECG retention in the tissue, and without causing dose-limiting side effects, we have developed an injectable and fast gelation hydrogel that can be specifically injected into infarcted hearts, can quickly solidify (<10 s) afte injection to efficiently retain ECG in the heart, and can gradually release ECG. Our preliminary in vivo study demonstrated that the hydrogel-based ECG release system attenuated cardiac fibrosis. Based on the above studies, we hypothesize that local delivery of hydrogel-based ECG release system into the infarcted heart will significantly attenuate cardiac fibrosis at different stages of post-MI, thus preventing cardiac function from progressive deterioration. The hypothesis will be tested through 2 specific aims: AIM #1 will test the hypothesis that optimal ECG release profiles will efficiently prevent cardiac fibroblasts from differentiating into myofibroblasts, and convert myofibroblasts back to cardiac fibroblasts. AIM #2 will test the hypothesis that ECG release systems will inhibit cardiac fibrosis from progressing in the infarcted hearts at different stages of post-MI to prevent progressive cardiac function deterioration.